Specificity of drug action

No drug is entirely specific in the sense that it acts exclusively only on

one type of cell or tissue, having just the desired effect and no other.

Drugs vary in their specificities and the usefulness of a drug clinically

is often directly related to its specificity.

Poison: a compound which has deleterious effects on cell function

without having any therapeutic effects. Eg., cyanide combines
strongly with the Fe3+ found in many proteins interfering in their
functioning.
Some drugs have absolutely no toxicity at concentrations used
clinically. Eg., penicillin inhibits a bacterial enzyme involved in the
formation of bacterial cell walls. Humans, lacking cell walls, are
unaffected by these concentrations of penicillin.
In between these two extremes (cyanide & penicillin) are many drugs
used clinically.

Methotrexate is a drug used in cancer chemotherapy and to treat

severe cases of psoriasis (using doses of 2.5 - 5 mg/kg). It acts by
inhibiting the rapid reproduction of epithelial cells in psoriatic plaques.
However, at slightly higher doses, methotrexate also inhibits
reproduction of mucosal cells in the intestine, which would lead to
ulceration and diarrhea.

Thus, useful drug actions are often accompanied by unwanted toxicity

due to side effects while non-selective toxicity gives rise to poisoning.
Generally, the useful, therapeutic effects of drugs may (?)
be separable from the toxic effects based on differences in
• their respective mechanisms of action
• their dose-response relationships if their mechanisms of action are
similar.
• the sites at which therapeutic and toxic effects are produced.

Attempts to increase the utility of a drug are based on improved

pharmacodynamic specificity (if the mechanisms of toxic and
therapeutic effects differ) or an enhanced pharmacokinetic selectivity
(distribution to the desired target site).
For specific drug:receptor interactions
to occur, the drug molecule must
have several points of attachment
to corresponding points on the
receptor molecule. The nature of
these points of attachment and their
relative positions and distances
apart are all critical for the drug’s
ability to combine with a receptor
and to produce a response.
Molecular features necessary for
acetylcholine action:
1. Positively charged N
2. Three CH3 groups attached to N
3. Ester linkage
4. Spacing between N and carbonyl C
Acetylcholine has actions at muscarinic and
nicotinic acetylcholine receptors, but many
other drugs act at one but not the other.
Why?
The acetylcholine molecule changes
its shape between cis and trans forms
(because it contains only single bonds
that do not limit rotation), and that
changes the distance between the N
atom and the carbonyl C. For binding
to the nicotinic acetylcholine receptor,
this distance should be about 3.5
angstroms, and for the muscarinic
receptor, it needs to be 5-7 angstroms.
Ligands specific to either the nicotinic
or muscarinic subtypes have
structures that limit intramolecular
rotation.
Antagonists at muscarinic and nicotinic acetylcholine
receptors have enough of the structural molecular
features that all them to bind to their respective
receptors, but not all the features that allow them to exert
a functional effect after binding.
These compounds (eg., atropine at muscarinic sites and
curare at nicotinic sites), have structures that limit
intramolecular rotation, thus preserving their selective
effects on these receptors.

Examples of other receptors showing such specificity are

 and  adrenergic receptors, nine types of serotonin
receptors, two major classes of GABA receptors (A and
B), and at least three major subtypes of opioid receptors
(,  and ).
Molecular selectivity of drugs binding to specific receptors
helps in the development of new therapeutic agents
displaying fewer side effects.
Raclopride is a highly selective antagonist at dopamine D2
and D3 (but not D1, D4 or D5) receptors. It is a potent
antipsychotic agent used in the treatment of schizophrenia.
Use of raclopride leads to fewer of the troublesome side
effects (eg., antipsychotic-induced Parkinsonism) that are
seen when all dopamine receptor subtypes are blocked.
The use of specific antagonists also helps in
understanding disease mechanisms. That D1 receptor
specific antagonists have no utility in the treatment of
schizophrenia tells us that dopamine actions at D1
receptors are not important in schizophrenia.
 Stereospecificity

Stereospecificity is not an
obligatory feature of receptor
selectivity for drugs but may add
significantly to it.
Many drugs have optically
isomeric forms in which only one
isomer is active, or one isomer
is considerably more potent than
the other. This is consistent
when at least three points of
attachment need to exist
between a receptor and its
ligand, and there exists either a
center or plane of asymmetry in
the drug.
 Examples of stereospecificity

• d- and l-hyoscyamine, of which only the l-form is active as a

muscarinic receptor blocker.

• Morphine has d- and l-forms, of which only the l-form has analgesic
activity, although both forms act as antitussives.

• Only the l-form of norepinephrine elevates blood pressure.

• d-amphetamine is a much more effective CNS stimulant than l-

amphetamine.
 Degrees of selectivity
An example of a drug with an extremely high degree of selectivity is
tetrodotoxin which binds only to Na+ channels, blocking action potential
propagation. There are also much less selective drugs. For example, the
structure
R-CH2-CH2-CH2-N-(CH3)2 enables a compound (at least to some extent)
to interact with receptors for histamine, acetylcholine and possibly
catecholamines. If the R-group is large, it can also function as an
antihistamine or a local anaesthetic.

For example chlorpromazine, procaine and

diphenhydramine share a number of
properties: they are all good local
anaesthetics, H1 receptor antihistamines and
myocardial antiarrythmics. However, unique
parts of each of their molecules also give
them pharmacological properties that are not
shared with the other compounds.
An example of how a
single molecular
structure can be
modified to yield a
number of different
drugs that have
differing and specific
actions.
 Pharmacokinetic selectivity

For those drugs that either do not act selectively on

particular receptors, or act on receptors that are
found on many cell types or tissues, selectivity can
still be obtained due to:
1. selective distribution of drug to an intended site
2. metabolic differences that make one tissue more
sensitive to the effect of the drug than another.
 Selectivity related to drug distribution
1. Topical application: egs., injection into abscess or joint cavity, or drops in the
eye. Selectivity arises from the fact that any drug absorbed systemically from
the site is diluted in a large volume of circulating blood. Vasoconstrictors may
increase usefulness.
2. Intra-arterial injection: useful for antitumour agents. Dissolving
chemotherapeutic in an oily carrier enables oily droplets to be trapped in
capillaries of the tumour and facilitates drug uptake into tumour cells.
3. Selectivity by ionization: Propantheline and atropine are both good muscarinic
blockers but the former does not cross the blood-brain barrier because it has a
quaternary N, which makes it a permanent cation.
4. Differential blood flow: Drugs given i.v. are initially primarily distributed to
tissues with high blood flow (remember VRG?). Thiopental, because it has a
high Pm/b value, will rapidly cross the blood-brain barrier as it is brought to the
brain.
5. Distribution by selective carriers: Eg., CD20 is a cell-surface antigen found on
90% of B-cell lymphomas but not normally on B-cells. 131I is linked to an
antibody to CD20 to radiate B-cell lymphomas.
6. Selective concentration by excretion: Many drugs are concentrated in urine
because they undergo glomerular filtration or secretion but are poorly re-
absorbed (eg. thiazides used as diuretics).
 Selectivity related to tissue differences

1. Selective cellular binding: Some drugs that are capable of acting on many
different types of cells if present in high enough quantities, show selectivity at
normal dosages when they bind to cellular components in certain cells. Eg.
quinine has a high affinity for malarial DNA.
2. Selective uptake by tissues: Some tissues can concentrate drugs. Eg. the
thyroid concentrates iodine, so 131I is concentrated in the thyroid in the
treatment of hyperthyroidism.
3. Selective intracellular activation: Some drugs are given as pro-drugs that
need to be bioactivated to function. If the tissue to be targeted has the ability
to convert the precursor to the active form, that increases selectivity. Eg.,
Enteric sulfonamides are bioactivated by gut bacteria to free sulfathiazole
which has antibacterial activity locally in the gut.
4. Selective tissue vulnerability: A drug may be relatively nonselective in terms of
the range of tissues it acts upon, yet may have therapeutic specificity if the
cellular function it affects is more important in one tissue than in the rest. Eg.,
Cardiac glycosides such as digoxin inhibit (Na++K+)-ATPase, but the heart
enzyme is more sensitive than that in skeletal muscle, liver, kidney, etc.
 Individual and species differences

Bacteria vs. host: Differential sensitivity between bacterial and animal

cells forms the basis for antibacterial therapy. Egs., (1) penicillin acts on
bacteria (that have cell walls), but not on animal cells. (2) Animal cells
take up folic acid but bacteria synthesize it and cannot take it up.
Sulfonamides act as competitive antagonists of PABA, a precursor of
folic acid.
Insects vs. mammals: Malathion is an organophosphate cholinesterase
inhibitor that is metabolized quickly in birds and mammals but slowly in
insects, yielding relatively specific toxicity to insects.
Genetic differences within species: Selective toxicity arising from genetic
variations within a species can be harmful , beneficial or both. A
hereditary deficiency of glucose-6-phosphate dehydrogenase renders
affected individuals sensitive to primaquine-induced hemolytic anemia,
but at the same time also makes them more resistant to the growth of
malaria in the liver.